1. Baclofen The GABA-B receptor agonist baclofen has been identified as a possible medication able to reduce alcohol craving and intake in alcohol dependent individuals. In keeping with preclinical studies, most of the clinical studies have demonstrated baclofens effects in reducing alcohol craving and intake (Addolorato et al, Lancet 2007, Alcohol Alcohol 2011; Leggio et al, Addict Behav 2012, Pharmacol Biochem Behav 2013). However, one trial found a robust treatment effect, but no differences between baclofen and placebo (Garbutt et al., ACER 2010). This suggests that different alcoholic individuals may respond differently to baclofen. Baclofen has been demonstrated to consistently reduce anxiety in alcoholic patients, and analyses of positive vs. null findings with baclofen suggest that alcoholic patients with higher levels of anxiety may represent a sub-population responsive to baclofen treatment (Leggio et al., CNS Neurol Disord Drug Targets 2010). Thus, the Section developed a clinical protocol (AA-13-0040) that is currently ongoing and that will systematically test the role of baclofen on alcohol-related outcomes in anxious alcoholic individuals. The design is a between-subject randomized double-blind controlled study with the medication conditions as the between subjects factor. Dr. Leggio received a NARSAD Award from the Brain & Behavior Research Foundation to conduct this study. 2. Ghrelin Ghrelin is a 28-amino acid peptide acting as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Animal experiments demonstrate that the central ghrelin action not only stimulates the reward processing but is also required for stimulation of that system by alcohol (Jerlhag et al., PNAS 2009; Suchankova et al., PLoS One 2013). Human studies show a positive correlation between ghrelin level and alcohol craving scores, and that intravenous ghrelin acutely increases alcohol craving in alcoholic individuals. Altogether, preclinical and clinical studies provide preliminary evidence that ghrelin might represent a novel pharmacological target for treatment (reviewed in: Leggio, Drug News Perspect 2010). There are three studies conducted or under way within this theme of the CPN Section research agenda. a. Recent previous studies from our group indicate that ghrelin administration may result in increased alcohol-seeking behaviors, such as cue-induced craving for alcohol (Leggio et al., Biol Psychiatry in press). However, there is no direct human evidence that ghrelin increases alcohol administration in humans. As such, we are currently conducting a within-subject, double-blind, placebo-controlled human laboratory study (AA-13-0043) whose primary objectives are to investigate whether IV ghrelin, as compared to placebo, increases motivation for alcohol reward, as measured by a progressive ratio schedule paradigm with IV alcohol self-infusion; and whether IV ghrelin, as compared to placebo, will increase the BOLD activation in the ventral striatum during an fMRI session. b. Unlike in rodents, the hypothesis that GHS-R antagonism results in reduced alcohol use as never been tested in humans. In order to test this hypothesis, we have developed a translational project that will assess the role of a GHS-R antagonist manufactured by Pfizer as a novel medication for alcoholism. This project was developed by Dr. Leggio in collaboration with Fatemeh Akhlaghi, Pharm.D., Ph.D., from URI and was recently awarded with a NCATS grant award. This project will allow us to generate preliminary evidence on the safety and efficacy of such pharmacological agent via three projects, i.e.: (P1) a set of experiments testing the effect of this drug in well-validated animal models of alcohol-seeking behavior; (P2) a drug/alcohol interaction study to establish safety in humans (Phase 1b); and (P3) a human laboratory proof-of-concept study to assess the efficacy of this drug on alcohol-seeking behaviors (Phase 2a). These are conducted at the NIH Intramural Program under the leadership of Dr. Lorenzo Leggio. The safety preclinical set of experiments is completed and shows no drug-alcohol interactions of potential concern. In parallel, we are conducting the Phase 1b study (14-AA-0042). We anticipate making a go/no-go decision related to the Phase 2a by the end of the calendar year. All three projects include PK/PD investigations conducted by Dr. Akhlaghi. c. We are collaborating with the NIDA Optogenetics and Transgenic Technology Core (Dr. Brandon Harvey) in order to develop conditioning knock-in and know-out rat models for the ghrelin receptor. We anticipate starting testing alcohol consumption and ghrelin antagonism in this model in 2015. 3. Oxytocin Recent research suggests that oxytocin (OT) may play a role in the neurobiology of AUD. Ethanol is a potent inhibitor of OT release and is neurotoxic to OT neurons. The behavioral deficits seen in chronic alcoholics suggest a central deficiency of OT. OT has low abuse liability and modulates a number of key systems involved in addiction processes, including dopamine (DA) mesolimbic reward circuitry. In animals, OT administration produced long-term decreases in alcohol reinforcement, decreased alcohol seeking during abstinence, attenuated drug tolerance, and decreased withdrawal symptoms. Furthermore, a pilot clinical study suggests a role of OT in reducing alcohol withdrawal symptoms and craving in alcoholic patients undergoing a detox. Dr. Mary Lee, MD, Staff Clinician in Dr. Leggios CPN Section was recently awarded with one of the NIH B2B Award to conduct translational studies on the role of OT in alcohol and drug addiction. The overall goal of this translational project is threefold: to demonstrate the effect, in subjects with AUD of intranasal OT on 1) alcohol cue-induced craving and self-administration, 2) alcohol induced striatal DA release and, 3) in a parallel preclinical study, to investigate the brain penetrance of intranasally-administered OT. The human component (T-AA-0031) will be a within-subject randomized, controlled study. In parallel, we will investigate the penetrance of exogenous intranasal OT into the brain and specific brain regions of binding in monkeys in collaboration with Dr. Bruno Averbeck (NIMH). Additionally, CPN is collaborating with: 1) Dr. Jenica Tapocik (NIAAA) to investigate the role of OT on alcohol-induced loss of right reflex (LORR); 2) Drs. Amy Newman and Gigi Tanda (NIDA) to investigate the role of OT in central dopamine release via microdialysis experiments; and 3) Dr. Marilyn Huestis to develop a very sensitive OT assay (liquid chromatography-tandem mass spectrometry). 4.GLP-1 The glucagon-like peptide-1 (GLP-1) is an incretin involved in the regulation of food intake. Recent preclinical studies have shown that a GLP-1 receptor (GLP1R) agonist, attenuates the reinforcing properties of alcohol in rodents (Egecioglu et al, Psychoneuroendocrinology 2013; Shirazi et al., PLoS One 2013). Given that AUD is a partly heritable, complex, psychiatric disorder, the Section designed a study aimed to investigate whether single nucleotide polymorphisms (SNPs) in GLP1R are associated with AUD. This study included (4) genetic association components and a reverse translational pharmacological experiment used to probe that GLP1R agonism is associated with reduced alcohol use (this last experiment conducted in collaboration with the NIAAA Extramural Division, Dr. Mark Egli). The main results of this study (Suchankova et al. manuscript submitted) indicated that genetic variation in the GLP1R were significantly associated with AUD. Additionally, the preclinical study indicated that GLP1R agonism results in significantly and dose-dependent reduction in alcohol consumption and that this is limited to ethanol-dependent mice.